Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures

描述(由申请人提供)：皮质骨孔隙率识别患有脆性骨折的糖尿病患者摘要这项赠款申请的广泛挑战领域是(03)生物标记物的发现和验证。定量成像技术由于其非侵入性，作为生物标记物获得了实质性的意义。这尤其适用于肌肉骨骼成像，其中成像生物标记物的开发是为了更好地了解骨骼结构和稳定性。因此，特殊挑战领域03-AR-102*侧重于开发新的成像(蛋白质组或基因组)方法，以确定脆性骨折的风险。该项目将定义和验证骨质量的新测量，这些测量比骨密度测量更具预测性。骨密度(BMD)是目前公认的预测骨质疏松骨折风险的骨生物标志物。双X射线骨密度仪(DXA)在区分有无骨折的受试者、预测骨折风险和监测治疗方面显示出良好的性能。然而，在某些疾病中，骨密度测量的局限性已经被认识到，在这些糖尿病骨疾病中具有突出的重要性。大量研究表明，虽然II型糖尿病患者的骨折风险增加，但糖尿病患者的骨密度也更高。这一悖论尚未得到很好的理解，也没有建立更好地评估糖尿病受试者骨折风险的具体诊断技术。美国国立卫生研究院此前创造了“骨质量”一词，以更好地描述那些不能很好地用骨量或骨密度来量化的骨强度实体。人们普遍认为，骨质量必须在糖尿病患者脆性骨折数量的增加中发挥核心作用，在骨质量指标中，侧重于皮质和松质骨结构的指标尤为突出。考虑到糖尿病日益增加的社会经济负担和脆性骨折对这些患者的破坏性后果，寻找一种强大的、非侵入性的骨质量生物标志物来更好地预测糖尿病患者的脆性骨折显然是一个主要的挑战领域。在最近的一项壁内研究试点项目中，我们能够研究糖尿病患者和非糖尿病对照组患者的骨结构参数。我们用定量CT(QCT)测量骨密度，并用高分辨率外周QCT(hr-pQCT)和高分辨率MRI研究皮质和松质骨结构。HR-pQCT是目前提供最佳各向同性空间分辨率(体素大小)以显示活体胫骨和桡骨远端皮质和松质骨结构的一种新的成像方式。我们的研究小组在这项技术方面积累了丰富的经验，特别是在图像后处理提取结构参数包括皮质孔隙度和有限元分析衍生的替代骨强度标志物方面。我们还对这些患者中的一组患者进行了腰椎的骨髓磁共振波谱分析，以确定骨髓脂肪的组成，因为这可能对了解糖尿病骨疾病的病理生理学有重要意义。这项研究的结果表明，尽管骨密度和骨小梁结构参数都不能区分脆性骨折和非骨折糖尿病患者组，但基于有限元分析的皮质骨孔隙率和参数存在显著差异。此外，糖尿病患者的骨髓脂肪含量也有高于正常对照组的趋势。这些发现需要通过对更大的患者群体的研究来证实，但可能对量化糖尿病受试者脆性骨折的风险具有重要意义。在这项拨款申请中，我们建议研究四个受试者组的皮质孔隙度，包括有无糖尿病和有无脆性骨折，以在临床上验证我们的初步研究中发现的结果。我们的假设是，使用hr-pQCT得出的皮质骨孔隙率和有限元分析的测量，以及mr波谱得出的骨髓脂肪，我们将能够区分糖尿病患者有和没有脆性骨折。我们还假设，与有和没有脆性骨折的非糖尿病患者相比，有脆性骨折的糖尿病患者的皮质骨结构不同，基于骨密度的参数将不能区分有骨折的糖尿病患者和没有骨折的糖尿病患者和对照组。考虑到糖尿病日益增加的社会经济负担和脆性骨折对这些患者的破坏性后果，寻找一种强大的、非侵入性的骨质量生物标志物来更好地预测糖尿病患者的脆性骨折显然是一个主要的挑战领域。我们相信，根据我们的初步数据，利用我们的新生物标志物，我们可能能够更好地表征糖尿病患者的骨折风险。

DESCRIPTION (provided by applicant): Cortical Bone Porosity Identifies Diabetes Subjects With Fragility Fractures Abstract The broad challenge area for this grant application is (03) Biomarker Discovery and Validation. Quantitative imaging techniques have, due to their non-invasive nature, gained substantial significance as biomarkers. This is in particular true for musculoskeletal imaging where imaging biomarkers are developed to better understand bone structure and stability. Thus the specific challenge area 03-AR-102* focuses on developing novel imaging (proteomic, or genomic) approaches to identify the risk for fragility fractures. This project will define and validate novel measures of bone quality that are more predictive than bone mineral density measurements. Bone mineral density (BMD) is currently the best-established bone biomarker to predict fracture risk in osteoporosis. Dual X-ray absorptiometry (DXA) has shown good performance in differentiating subjects with and without fractures, predicting fracture risk and monitoring therapy. However, in certain disease entities limitations of BMD measurements have been acknowledged and among these diabetic bone disease is of outstanding importance. A large number of studies have shown that while fracture risk in subjects with type II diabetes is increased, diabetics also have a higher BMD. This paradox has not been well understood and specific diagnostic techniques to better assess fracture risk in diabetic subjects have not been established. The NIH has previously coined the term "bone quality" to better characterize entities of bone strength which are not well quantified with bone mass or BMD. It is generally accepted that bone quality must play a central role in the increased number of fragility fractures in diabetics and among the measures of bone quality those focusing on cortical and trabecular bone architecture are outstanding. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. In a recent intramural research pilot project we were able to study bone structure parameters in diabetic subjects with and without low energy fractures and non-diabetic controls. We obtained BMD measurements using quantitative CT (QCT) and studied cortical and trabecular bone structure with high resolution peripheral QCT (hr-pQCT) and high resolution MRI. Hr-pQCT is a novel imaging modality currently providing the best isotropic spatial resolution (voxel size) to visualize cortical and trabecular bone structure in vivo at the distal tibia and radius. Our research group has acquired extensive experience with this technique, in particular concerning image post-processing to extract structural parameters including cortical porosity and finite element analysis derived surrogate markers of bone strength. We also performed bone marrow MR spectroscopy of the lumbar spine in a subset of these patients to characterize bone marrow fat composition, as this may be of significant importance in understanding pathophysiology of diabetic bone disease. The results of this study showed, that while neither BMD nor trabecular structure parameters were able to differentiate fragility fracture and non-fracture diabetic patient groups, substantial, significant differences in cortical bone porosity and parameters based on finite element analysis were found. Also a trend was found for higher bone marrow fat in diabetic subjects versus normal controls. These findings need to be confirmed by studying larger patient groups, yet could potentially have substantial implications for quantifying risk of fragility fractures in diabetic subjects. In this grant application we propose to study cortical porosity in four subject groups, with and without diabetes and with and without fragility fractures to clinically validate the results found in our pilot study. Our hypothesis is that using hr-pQCT derived measures of cortical bone porosity and finite element analysis as well as MR spectroscopy derived bone marrow fat we will be able to differentiate diabetic subjects with and without fragility fractures. We also hypothesize that diabetic subjects with fragility fractures will have different cortical bone structure compared to non-diabetic subjects with and without fragility fractures and that BMD based parameters will not be able to differentiate diabetics with fractures versus diabetics and controls without fracture. Finding a strong, non-invasive bone quality biomarker to better predict fragility fractures in diabetic patients is clearly a major challenge area, given the increasing socio-economical burden of diabetes and the devastating consequences of fragility fractures in these patients. We believe, based on our preliminary data, that with our novel biomarkers we may be able to better characterize fracture risk in diabetic patients.